The long term aim of this project is to study certain aspects of choline metabolism in the pathogenesis of dementia of the Alzheimer type (DAT). The strategy will be to investigate some abnormalities for erythrocyte choline transport which have been demonstrated in some patients with DAT with the hypothesis that this dysfunction reflects similar abnormalities occurring in the central nervous system. In addition, the peripheral and central nervous systems of animals made hypocholinergic with a false choline (Ch) analogue will be studied and compared to patients with DAT. More specifically, choline transport and metabolism will be studied in erythrocytes from patients with Alzheimer's disease using stable isotopic tracer techniques. Red blood cell (RBC) Ch levels will be measured in patients with DAT and compared to age-matched demented and normal controls. Influx and efflux of Ch between erythrocytes and medium as well as Ch release and uptake from erythrocyte membrane will be calculated. An attempt will be made to discriminate between a plasma factor and an inherent RBC defect by cross-incubation studies in which plasma from DAT patients with abnormal erythrocyte choline and influx will be incubated with erythrocytes from normal subjects and from patients with DAT who show no erythrocytic abnormalities. If the normal erythrocytes develop abnormal Ch levels or influx, it would suggest that this abnormality in DAT patients is due to a plasma factor. An attempt to characterize this factor would be attempted. Families with an autosomally dominant inherited pattern of DAT will be studied. Families members with DAT will be compared to unaffected relatives at risk to see if abnormal erythrocyte Ch is a marker for DAT throughout life or increases as the disease deteriorates clinically. A potential animal model of Alzheimer's disease will be studied using the false choline analogue N-amino, N,N-dimethyl-aminoethanol(NADe). This will be fed to young rats on a choline-deficient diet, which leads to the incorporation of this false precursor into both acetylcholine (ACh) and membrane phospholipids (unpublished data). Erythrocyte flux, neurochemical parameters, and behavioral and histopathological studies will be conducted in these rats, and compared to control animals fed a diet containing an equal concentration of choline instead of NADe.